Polyomaviruses are DNA-based (double-stranded DNA, ~5000 base pairs, circular genome) viruses. They are small (40–50 nanometers in diameter), and icosahedral in shape, and do not have a lipoprotein envelope. Moreover, the genome possess early and late genes, contributing to its complex transcription program. They are potentially oncogenic (tumor-causing); they often persist as latent infections in a host without causing disease, but may produce tumors in a host of a different species, or a host with an ineffective immune system. The name polyoma refers to the viruses' ability to produce multiple (poly-) tumors (-oma).

Until recently, the family of Polyomaviridae contained only one genus (Polyomavirus). The recent expansion of known Polyomaviruses called for reclassification of the family into 3 genera: Orthopolyomavirus, Wukipolyomavirus, and Avipolyomavirus.[1]

For nearly 40 years, only two polyomaviruses were known to infect humans. Genome sequencing technologies have recently discovered seven additional human polyomaviruses, including one causing most cases of Merkel cell carcinoma and another associated with Trichodysplasia spinulosa associated-virus (TSV), that are natural infections of humans. Discovery of these polyomaviruses and other new—but previously undiscovered—viruses may provide clues to the etiologies for human diseases.[citation needed]

Polyomaviruses have been extensively studied as tumor viruses in humans and animals, leading to fundamental insights into carcinogenesis, DNA replication and protein processing. The tumor suppressor molecule p53 was discovered, for example, as a cellular protein bound by the major oncoprotein (cancer-causing protein) T antigen made by Simian vacuolating virus 40 (SV40). The avian polyomavirus sometimes referred to as the Budgerigar fledgling disease virus is a frequent cause of death among caged birds.

The classification of Polyomaviruses is constantly evolving due to the explosion of newly discovered viruses. Previously, the family of Polyomaviridae was divided into three major clades (genetically-related groups)—the SV40 clade, the avian clade, and the murine polyomavirus clade:[3] Recent reclassification by the International Committee on Taxonomy of Viruses (ICTV) recommended dividing the family of Polyomaviridae into three genera:[1]

Genus Orthopolyomavirus (type species SV40)

Genus Wukipolyomavirus (type species KI polyomavirus)

Genus Avipolyomavirus (type species Avian polyomavirus)

Many of the known viruses have not been fully classified or have not yet been officially accepted; hence, the taxonomy of this family is on going.

The genome is circular, composed of double stranded DNA and has six genes: large T, small t, viral protein 1 (VP1), viral protein 2 (VP2), and viral protein 3 (VP3) and agnoprotein. It is about 5 kilobase pairs in length. VP1-3 form the viral capsid.

Prior to genome replication, the processes of viral attachment, entry and uncoating occur. Cellular receptors for polyomaviruses are sialic acid residues of gangliosides. The attachment of polyomaviruses to host cells is mediated by viral protein 1 (VP1) via the sialic acid attachment region. This can be confirmed as anti-VP1 antibodies have been shown to prevent the binding of polyomavirus to host cells.[10]

Polyomavirus virions are subsequently endocytosed and transported first to the endoplasmic reticulum where a conformational change occurs revealing Vp2.[citation needed] Then by an unknown mechanism the virus is exported to the nucleus.[citation needed]

Polyomaviruses replicate in the nucleus of the host. They are able to utilise the host’s machinery because the genomic structure is homologous to that of the mammalian host. Moreover, the promoter sequence of Polyomavirus' promoter sequence is a strong attractant for the host's RNAP. Viral replication occurs in two distinct phases; early and late gene expression, separated by genome replication.[citation needed]

Early gene expression is responsible for the synthesis of non-structural proteins. Since Polyomaviruses rely on the host to control both the gene expression, the role of the non-structural proteins is to regulate the cellular mechanisms. Close to the N terminal end of polyomavirus genome are enhancer elements which induce activation and transcription of a molecule known as the T-antigen (see SV40 Large T-antigen). Early mRNA’s, encoding T-antigen are produced by host RNA polymerase II. T-antigen autoregulates early mRNA’s, subsequently leading to elevated levels of T-antigen. At high concentrations of T-antigen, early gene expression is repressed, triggering the late phase of viral infection to begin.[citation needed]

Genome replication acts to separate the early and late phase gene expression. The duplicated viral genome is synthesised and processed as if it were cellular DNA, exploiting the host’s machinery. As the daughter viral DNA are synthesised they associate with cellular nucleosomes to form structures that are often referred to as "minichromosomes". In this manner the DNA is packaged more efficiently.[citation needed]

Late gene expression synthesises the structural proteins, responsible for the viral particle composition. This occurs during and after genome replication. As with the early gene expression products, late gene expression generates an array of proteins as a result of alternative splicing.[citation needed]

Within each viral protein are 'nuclear localization signals' which cause the viral proteins to amass in the nucleus. Assembly of new virus particles consequently occurs within the nucleus of the host cell.[11]

Release of newly synthesized polyomavirus particles exit the infected cell by one of two mechanisms. Firstly and less commonly, they are transported in cytoplasmic vacuoles to the plasma membrane, where budding occurs. More frequently, they are released when the cell lyses due to the cytotoxicity of virus particles present in the infected cell.[citation needed]

The large T-antigen plays a key role in regulating the viral life cycle by binding to the viral origin of DNA replication where it promotes DNA synthesis. Also as the polyomavirus relies on the host cell machinery to replicate the host cell needs to be in s-phase for this to begin. Due to this, large T-antigen also modulates cellular signaling pathways to stimulate progression of the cell cycle by binding to a number of cellular control proteins.[12] This is achieved by a two prong attack of inhibiting tumor suppressing genes p53 and members of the retinoblastoma (pRB) family,[13] and stimulating cell growth pathways by binding cellular DNA, ATPase-helicase, DNA polymerase α association, and binding of transcription preinitiation complex factors.[14] This abnormal stimulation of the cell cycle is a powerful force for oncogenic transformation.

The small T-antigen protein is also able to activate several cellular pathways that stimulate cell proliferation. Polyomavirus small T antigens commonly target protein phosphatase 2A (PP2A),[15] a key multisubunit regulator of multiple pathways including Akt, the mitogen-activated protein kinase (MAPK) pathway, and the stress-activated protein kinase (SAPK) pathway.[16][17]Merkel cell polyomavirus small T antigen encodes a unique domain, called the LT-stabilization domain (LSD), that binds to and inhibits the FBXW7E3 ligase regulating both cellular and viral oncoproteins.[18] Unlike for SV40, the MCV small T antigen directly transforms rodent cells in vitro.[19]

Several polyomaviruses have been found in humans. Four of these viruses (JC virus, BK virus, KI virus and WU virus) are closely related to SV40 and infection with these viruses can be confused with SV40 infection.[21][22]Merkel cell polyomavirus (MCV) is highly divergent from the other human polyomaviruses and is most closely related to murine polyomavirus. Trichodysplasia spinulosa-associated polyomavirus (TSV) is distantly related to MCV. Two viruses—HPyV6 and HPyV7—are most closely related to KI and WU viruses, while HPyV9 is most closely related to the African green monkey-derived lymphotropic polyomavirus (LPV).

BK virus produces a mild respiratory infection and can affect the kidneys of immunosuppressed transplant patients. Both of these viruses are very widespread: approximately 80 percent of the adult population in the United States have antibodies to BK and JC.

Two polyomaviruses, KI (Karolinska Institute)[23] and WU (Washington University)[24] viruses, are closely related to each other and have been isolated from respiratory secretions. These viruses, discovered almost simultaneously in 2007, were the first of an expanding group of polyomaviruses found to naturally infect humans beyond JCV and BKV.

In 2010, three new polyomaviruses infecting skin were discovered: HPyV6 and HPyV7:[28] these two viruses are as yet not associated with human disease. Trichodysplasia spinulosa-associated polyomavirus (TSV) was discovered in the proliferative skin lesion termed trichodysplasia spinulosa seen in immunosuppressed patients.[29][29] All three of these viruses were discovered by rolling circle amplification of human skin DNA that preferentially amplifies small circular genomes, such as polyomaviruses.

In March 2011, a ninth polyoma virus, HPyV9, related to a monkey lymphotropic virus (LPV), was cultured from the blood of immunosuppressed patients. The finding partially explains why some humans had antisera cross-reactive with monkey LPV but none of the known human polyomaviruses cross-reacted with those patients' sera.[30]

In 2012, a new polyoma virus (Malawi polyomavirus—MWPyV) was isolated from the stool of a healthy child from Malawi.[7] This virus has also been isolated in St. Louis, Missouri. It appears to be highly divergent from other members of this virus family.

In 2012, another polyoma virus—MX polyomavirus—was isolated from stool samples.[32] This virus was isolated from samples from California, Chile and Mexico. This virus was also isolated from a respiratory tract infection in Mexico. Its potential for pathogenicity (if any) is currently unknown.

In 2013, a new polyoma virus (human polyomavirus 12) was found in resected liver tissue.[33] Subclinical infection with this virus appears to be common (10–20% of asymptomatic population).

In 2013, a new polyoma virus—STL polyomavirus—was isolated from human faeces.[6]

All the polyomaviruses are highly common childhood and young adult infections.[34] Most of these infections appear to cause little or no symptoms. These viruses are probably lifelong persistent among almost all adults. Diseases caused by human polyomavirus infections are most common among persons who become immunosuppressed by AIDS, old age or after transplantation and include Merkel cell carcinoma, PML and BK nephropathy.

The SV40 replicates in the kidneys of monkeys without causing disease, but causes sarcomas in hamsters. It is highly controversial whether it can cause disease in humans since the virus may have been introduced into the general population in the 1950s through a contaminated polio vaccine. Thus far, no widely accepted evidence for the virus being present in human cancer has been reported although reports for it being present in pleural mesothelioma, some nonHodgkin's lymphomas and other human cancers have been published. This is confounded by the high level of cross-reactivity for SV40 with known human polyomaviruses (BK virus and JC virus) that are widespread and by common use of SV40 DNA as a near universal reagent in scientific laboratories.[22] Most virologists dismiss SV40 as a cause for human cancers.[21]

BK viral genomes have been found in benign and malignant prostate tissue.[41] It has been suggested that this virus may play a role in the development of malignancy but further work in this area is required.

The diagnosis of polyomavirus almost always occurs after the primary infection as it is either asymptomatic or sub-clinical. Antibody assays are commonly used to detect presence of antibodies against individual viruses.[42] Competition assays are frequently needed to distinguish among highly similar polyomaviruses.[43]

In cases of progressive multifocal leucoencephalopathy (PML), a cross-reactive antibody to SV40 T antigen (commonly Pab419) is used to stain tissues directly for the presence of JC virus T antigen. PCR can be used on a biopsy of the tissue or cerebrospinal fluid to amplify the polyomavirus DNA. This allows not only the detection of polyomavirus but also which sub type it is.[44]

There are three main diagnostic techniques used for the diagnosis of the reactivation of polyomavirus in polyomavirus nephropathy (PVN): urine cytology, quantification of the viral load in both urine and blood, and a renal biopsy.[42] The reactivation of polyomavirus in the kidneys and urinary tract causes the shedding of infected cells, virions, and/or viral proteins in the urine. This allows urine cytology to examine these cells, which if there is polyomavirus inclusion of the nucleus, is diagnostic of infection.[45] Also as the urine of an infected individual will contain virions and/or viral DNA, quanitation of the viral load can be done through PCR.[46] This is also true for the blood.

Renal biopsy can also be used if the two methods just described are inconclusive or if the specific viral load for the renal tissue is desired. Similarly to the urine cytology, the renal cells are examined under light microscopy for polyomavirus inclusion of the nucleus, as well as cell lysis and viral partials in the extra cellular fluid. The viral load as before is also measure by PCR.[citation needed]

Tissue staining using a monoclonal antibody against MCV T antigen shows utility in differentiating Merkel cell carcinoma from other small, round cell tumors.[47] Blood tests to detect MCV antibodies have been developed and show that infection with the virus is widespread although Merkel cell carcinoma patients have exceptionally higher antibody responses than asymptomatically infected persons.[48][49][50][51]